Oxidation of an allo-yohimbine compound to a 3-dehydro-yohimbene compound



United States Patent Ofiice Patented Feb. 4, 1964 The present invention concerns process for the oxidative introduction of a double bond. More especially, it relates to the conversion of a compound having the 1,3a,5,6,14, l5,16,17,18,19,20,21 dodecahydro-benz[g]indo1o[2,3-a]- quinolizine ring system of the formula into the 3(14)-dehydro-derivatives thereof having the ring system of the formula ie. the 1,5,6;;15,16,17;18,19,20,2l-decahydro-benz[g]inidolo[2,3-a]quinolizine ring system, or salts of such compounds, in which the double bond extends from the 3- position to the 4-position, and which have the ring system of the formula which ring system is also present, whenever the free 3 14) dehydro compound is dissolved in a polar solvent.

The 1,3/3,5,6,l4,15,16,17,18,19,20,21-dodecahydrobenz- [g]indolo[2,3-a]quinolizine ring system of the formula is common to a number of pharmacologically active compounds or important intermediates.

2 For example, l8-hydroxy-1,3,B,5,6,14,15a,16a,17,18,19, 20a,2 l dodecahydro-benz [g] indolo 2,3 -a]quinolizi11e 16,3- carboxylic acid compounds, i.e. l8-hydroxy-3-epi-alloyohirnbane 16/3-carboxylic acid compounds, having the ring system of the formula or monoesters, diesters, monoethers or monoester-monoethers thereof, are especially useful as pharmacolo-gically effective compounds or intermediates for the preparation of the latter. For example, diesters of l8fi-hydroxy-l7a- R-3-epi-allo-yohimbane lofl-carboxylic acids, in which R stands primarily for lower alkoxy, as well as hydrogen or cyano, particularly those, in which the 16B-carboxyl group is esterified with an aliphatic alcohol and the ISfl-hydroxyl group is esterified by an organic carboxylic acid, and rnonoester-monoethers of 18-hydroxy-17a-R-3-epi-alloyohimbane 16/3-carboxylic acids, in which the 16,8-carboxyl group is esterified with an aliphatic alcohol, and the 18-hydroxyl group (having either the reconfiguration or the [i-configuration) is etherified with an aliphatic alcohol, have antihypertensive, sedative and/ or antifibrillatory effects and are used accordingly. The corresponding free acids, the monoesters, the monoethers and certain diesters, particularly those in which the 18-hydroxyl group (having either the O(.- or the fl-conliguration) is esterified wth an organic sulfonic acid or a hydrohalic acid, are important intermediates in the manufacture of the pharmacologically active compounds.

Useful intermediates, shaving the 18-hydroxy-3-epi-alloyohirnbane l6/3-carboxylic acid ring system, are, for example, 1S-hydroxy-17a-R-3-epi-allo-yohimbane 16fi-carboxylic acids, in which the l8-hydroxyl group may have either the OL-COIIfigllI'atlOH or the fl-config uration, and R has the previously-given meaning, e.g. reserpic acid, deserpidic acid, 18epi-reserpic acid and the like, 18-hydroxy- 17o-R-3-epi-allo-yohim bane 16fl-carboxylic acid esters, in which the 18-hydroxyl group may have either the oa-configuration or the B-configuration, R has the previouslygiven meaning, and the 16fl-carboxyl group is esterified With an aliphatic alcohol, particularly a lower alkanol, e.g. lower alkyl reserpa-tes, lower alkoxy-lower alkyl reserpates, lower alkyl deserpidates, lower alkyl 18-epi-reserpates, lower alkoxy-lower al-kyl 18-epi-reserpates and the like, or 18 organic sulfonyloxy-17a-R-3-epi-allo-yohimbane 16,8-carboxylic acid esters, in which the 18-organic sulfonyloxy group has either the oc-COILfiglll'titiOIl or the fi-configuration, R has the previously-given meaning, and the 16fl-carboxyl group is esterified with an aliphatic alcohol, particularly a lower alkanol, e.g. lower alkyl 18-O-organic sulfonylareserpates, lower alkoxy-lower alkyl 18-O-organic sulfonyl-reserpates, lower alkyl 18-epi-O- organic sulfonyl-reserpates, lower alkoxy-lower alkyl 18 epi-O-organic sulfonyl-reserpates and the like. Pharmacologically useful compounds, which may be prepared from such intermediates according to known methods, are, for example, 18B-organic carbonyloxy-l7a-R-epi-alloyohirnbane l6fl-carboxylic acid esters, e.g. esters of lower alkyl reserpates and lower alkyl deserpidates with monocyclic carbocyclic aryl carboxylic acids or monocyclic carbocyclic aryl-lower aliphatic carboxylic acids, e.g. reserpine, syrosingopine, deserpidine, reseinnamine and the like, or 18-etherified hydroxy-17e-R-3-epi-allo-yohimbane l6 3-carboxylic acid esters, in which the IS-etherified hydroxyl group (having either the tat-configuration or the fi-configuration) is etherified With an aliphatic alcohol, particularly a lower alkanol, R has the previously-given meaning, and the 16,6-carboxyl group is esterified with an aliphatic alcohol, particularly a lower alkanol, e.g. lower alkyl 18-O-lower alkyl reserpates, lower alkyl 18-epi-O- lower alkyl-reserpates, lower alkoxy-lower alkyl 18epi- O-lower alkoxy-lower alkyl-reserpates and the like.

Compounds having the 1,3,8,5,6,l4,15,l6,l7,18,l9,20,2ldodecahydro-benz[g]indolo[2,3-a]quinolizine ring system, especially compounds of the 18-hydroxy-l,3fl,5,6,14, a,16et,l7,l8,l9,20oc,21 dodecahydro benz[g]indolo[2, 3-a]quinolizine 16,6-carboxylic acid or l8-hydroxy-3-epiallo-yohimbane 16,8-carboxylic acid series, may be prepared, for example, by extracting plant material (roots, barks, seeds and the like) from certain plants of the Apocynacea family, such as those of the genus Rauwolfia, e.g. Rauwolfia serpentina, Rnuwolfia vomiloria, Rauwolfia inebrl'mzs, Rauwolfia tetraphylla, Rauwolfia canescens, Rauwolfia lzirsuta and the like, Tondusia, e.g. T ondusia longifolia and the like, or Alstonia, e.g. Alstolzia constrfcta and the like, which contain alkaloids having the abovementioned ring systems, such as reserpine, rescinnamine, deserpidine and the like. These alkaloids may be used per se or may be converted into suitable starting materials and intermediates, from which other pharmacologically useful products can be derived.

In view of the fact that dependency on natural sources foreign to main manufacturing areas always presents problems of adequate supply, the total synthesis of the natural alkaloids or analogs thereof, using readily available starting materials, is important and highly desirable. Woodward et al., J. Am. Chem. Soc., vol. 78, p. 2023 (1956) has described the total synthesis of reserpine which, upon completion of minor modifications, has proven to be well-suited for the preparation of the natural alkaloid and analogs thereof, having pharmacological properties or serving as intermediates. A key intermediate in the specific synthesis of Woodward et al. is a salt of methyl l8-O-acetyl-3 (4)-dehydro-reserpate, which may be converted into the free base, i.e. methyl IS-O-acetyl- 3(l4)-dehydro-reserpate, by treatment with ammonia; this salt is formed by ring closure of methyl l8-O-acetyl- 2,3-seco-reserpate with an acidic reagent, e.g. phosphorus oxychloride. Removal of the double bond extending from the 3-position represents a major problem, because reduction can lead to the formation of two isomeric substances, of which the one with the more stable configuration, i.e. methyl l8-O-acetyl-3-iso-reserpate, represents at least a major by-product, if not the major product of the reduction. Woodward et al., in completing the synthesis, treats the methyl 18-O-acetyl-3-dehydro-reserpate salt with sodium borohydride to form exclusively the more stable methyl l8-O-acetyl-3-iso-reserpate; upon total hydrolysis to 3-iso-reserpic acid, lactone formation, epimerization by treatment with pivalic acid and subsequent reesterification, this compound is transformed into the desired reserpine or an analog thereof.

In view of this rather lengthy procedure, which, above all, involves total hydrolysis of a diester intermediate and reesterification of a hydroxy-acid to a diester, ways and means have been explored to ([1) reduce a 3-dehydroderivative to the compound having the desired 3fi-configuration, or (b) directly convert a resulting compound having the more stable zit-configuration into compounds having the desired fl-configuration at the 3-position.

Direct reduction (variation a) of compounds having the 1,5,6,l50t,l6ct,l7,18,19,200t,21 decahydro-benz[g]indolo[2,3-a] quinolizine structure, or salts thereof, has been described by Weisenborn et al., J. Am. Chem. Soc., vol. 78, p. 2022 (1956); these authors treat a A -allo-yohimbene compound with zinc in 50 percent aqueous acetic acid to form a mixture of the desired 3-epi-allo-yohimbane and the isomeric allo-yohimbane compound, the latter having the 3a-configuration and being the main product of such reduction. A more advantageous precedure, described by Bardoneschi et al., U.S. Patent No. 2,924,600, involves treatment of the solution of a M-allo-yohimbene compound in a mixture of water and a water-miscible organic solvent with zinc in the presence of aqueous perchloric acid; according to this method up to percent of the compound having the desired 3,8-configuration is obtained, the by-product being mainly the corresponding compound having the 3a-configuration. It is, therefore, clear that, according to the known reducing procedures, substantial amounts of undesired product having the m-configuration in the 3-position of the l,3a,5,6,l4,l5,l6, 17,18,19,20,21 dodecahydro benz[g]indolo[2,3-a]quinolizine ring system are obtained; the conversion of the byproduct into a useful compound having the 3fl-configuration is, therefore, desirable.

Direct conversion (variation b) of compounds having the 1,30t,5,6,14,15,16,17,l8,19,20,21 decahydro-benz[g] indolo[2,3-a]quinolizine structure into compounds, in which the hydrogen in the 3-positon has the fi-configuration, for example, of an allo-yohimbane into a 3- epi-allo-yohimbane compound, has been reported. For example, by treating a compound of the allo-yohimbane series with a suitable acid, such as acetic acid and the like, according to the disclosure of U.S. Patent No 2,957,877, an equilibrium between the allo-yohimbane compound and the desired 3-epi-allo-yohimbane compound can be established, and the latter can be isolated from the equilibrium mixture. However, the yields obtained according to this procedure are not satisfactory, unless the recovered starting material is recycled several times, which tends to make the procedure lengthy and subject it to losses.

In View of the fact that compounds having the l,3ot,5,6, 14,l5,l6,17,l8,19,20,21 dodecahydro benz[g]indolo[2, 3-a]quinolizine ring system, particularly those of the 18- hydroxy 1,30t,5,6,l4,150t,l60t,17,lS,l9,2OC,2l-lOdCCahydro-benz[g]indolo[2,3-a]quinolizine 16,9-carboxylic acid or 18-hydroxy-3-epi-allo-yohimbane 16B-carboxylic acid series, are easily prepared or are formed as major byproducts in the preparation of compounds having l,3/3,5, 6,l4,l5,i6,17,18,19,20,2l dodecahydro'benflg]indolo[2, 3-a]quinolizine ring system, conversion (or reconversion, in case they are formed during the reduction of a 3-dehydro-compound) of the former into the corresponding 3- dehydro-compounds, having the l,5,6,15,16,17,l8,19,20, 2l-deeahydro-benz[g]indolo[2,3-a]quinolizine ring sys tem, particularly into compounds of the 18-hydroxy-l,5,6, 15a,16a,l7,18,19,20a2l decahydro benz[g]indolo[2,3- a]quinolizine l6fi-carboxylic acid or A -l8-hydroxy-alloyohimbene -carboxylic acid series, or salts thereof, and subjecting these B-dehydro-compounds to one of the previously-mentioned procedures to form the compounds having the desired l,3fl,5,6,14,15,16,17,18,l9,20,21-dodecahydro-benz[g]indolo[2,3-a1quinolizine ring system, therefore, appears to offer the most conventient method of utilizing the undesirable by-products of the total synthesis.

Several procedures dealing with this problem have been disclosed, but none of them offers completely satisfactory results. For example, Weisenborn et al., J. Am. Chem. Soc., vol. 78, p. 2022 (1956), described the use of mercuric acetate as an oxidation reagent; however, it is known that the work-up of mixture resulting from such mercuric acetate oxidation procedures are tedious, and, in order to completely remove all traces of mercury compounds, involve the use of poisonous hydrogen sulfide to precipitate mercuric sulfide. Furthermore, the resulting product is generally a mixture containing starting materials and products which have a higher degree of oxidation.

Gottfredsen et al., Acta Chem. Scand, vol. 10, p. 1414 (1956), suggest the use of tertiary butyl hypochlorite as: the reagent to convert a yohimbane compound into its,

A -yohimbene derivative; however, this reagent requires the use of organic diluents which, if possible, are avoided in manufacturing procedures in View of their volatility, inflammability and the like.

A recently disclosed procedure (US. Patent No. 2,957,000) involves refluxing a solution of a yohimbane compound in acetic acid in the presence of palladium black and in the atmosphere of an inert gas to form the A -yohimbene compound. This procedure, again, is not very suitable for technical use; refluxing acetic acid and exclusion of air-oxygen require special equipment and, again, the reaction is carried out in a completely organic solvent. Obviously, the above-described procedures are unsatisfactory.

An object of the present invention is to provide a simple process for the conversion of compounds having the 1,30c,5,6,14,15,16,17,18,l9,20,21 dodecahydro benz[g] indolo[2,3-a]quinolizine ring system into the corresponding dehydro compounds having a double bond extending from the 3-position, or salts thereof, which process does not require special equipment, is carried out in an aqueous medium and at room temperature, and proceeds in excellent yields. 7

Other objects and advantageous features thereof will become apparent as the description proceeds.

We have now found, that the oxidative introduction of a double bond extending from the 3-position into a compound having the 1,3a,5,6,14,15,16,l7,18,19,20,2l-dodecahydro-benz[g]indolo[2,3-a] quinolizine ring system to form the corresponding 3-dehydro-compound according to our invention is carried out by treating a compound having the 1,3oc,5,6,14,15,16,17,18,19,20,21 dodecahydrobenz[g]indolo[2,3-a]quinolizine ring system, or a salt thereof with an oxidation reagent containing hexavalent chromium, and, if desired, converting a resulting salt into a free compound, and/or, if desired, converting a resulting base into a salt thereof.

Preferred oxidation reagents containing hexavalent chromium are salts of chromic acid, such as alkali metal dichromates, particularly potassium dichromate and the like, as well as ammonium dichromate, or any other analogous salt containing the hexavalent chromium. Also useful as an oxidation reagent is chromic anhydride or any other suitable, analogous oxidation reagent of the above type. These reagents are advantageously used in the presence of an acid, especially acetic acid and the like, which may also serve as a diluent.

The reaction is carried out in an aqueous medium, preferably in a mixture of water and water-miscible organic solvents. The latter are diluents, which are not oxidized by the oxidation reagent; suitable solvents are, for example, tetrahydrofuran, p-dioxane, acetone and the like, but preferably acetic acid. The latter, when used as a diluent may also serve as an acidic reagent which may be required whenever the oxidation reagent is used in an unreactive form.

The reaction is carried out at room temperature, if necessary, while cooling.

Preferably, the oxidative introduction of the double bond into the starting material is carried out at room temperature using a salt of chromic acid, such as an alkali metal dichromate, especially potassium dichromate, as the oxidation reagent, in a mixture of water and a watermiscible organic solvent, especially in aqueous acetic acid.

The 3-dehydro-compound resulting from the above procedure is preferably isolated by neutralizing or basifying the reaction mixture, thus converting a resulting salt formed in the acidic reaction medium into the free base. Any water-soluble alkaline reagent maybe used for that purpose; especially convenient is ammonia in the form of a concentrated aqueous solution thereof. Upon basifying the reaction mixture, the desired base may precipitate and be filtered 01?, or it may be extracted from the aqueous medium into an organic, sparingly water-miscible solvent, e.g. methylene chloride, chloroform, diethyl ether and the like, and thus be separated from the reaction mixture.

A resulting base may be converted into a salt thereof by treatment with an acid according to known methods, such as, for example, with inorganic acids, e.g. hydrochloric, hydrobromic, perchloric, nitric, thiocyanic, sulfuric, phosphoric acid and the like, or with organic acids, e.g. acetic, propionic, oxalic, malonic, succinic, maleic, hydroxymaleic, dihydroxymal-eic, fumaric, malic, tartaric, citric acid and the like, or with organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, Z-hydroxyethane' sulfonic, benzene sulfonic, p-toluene sulfonic acid and the like. Especially preferred salts are those, which are subsequently used in the reduction procedure for the conversion of the resulting 3-dehydro-compound's into the compounds having the 1,3,3,5,6,14,l5,16,17,18,19,20,2ldodecahydro-benz[g]indolo[2,3-a]quinolizine ring system; such salts are, particularly, the perchlorates, which 'may be prepared by treatment with perchloric acid.

'In a resulting 3-dehydro-compound, the double bond extends from the 3-position to the 4-position, whenever said compound is present in the form of a salt thereof or whenever the free base is in solution with a polar solvent. It extends from the 3-position 'to the l4-position, whenever the'3- dehydro-compound is in the form of the free base or whenever the latter is in solution with a slightly polar to non-polar solvent.

Starting materials used in the procedure of this inventionare particularly the compounds of the 18-hydroxy- 1,3 t1,5, 6 ,1 4,15tl,160t,17,18,19,200t,21 dodecahydro -benz [g]indolo[2,3 a]quinolizine 16,8-carboxylic acid or 18- hydroxy-allo-yohimbane 16,8-carboxylic acid series, having the formula oit' especially those of the 18-hydroxy-l'Za-R-allo-yohimbane IGB-carboxylic acid series, in which R has the previouslygiven meaning and stands primarily for lower alkoxy. The starting materials used in the above reaction are, therefore, 18 -hydroxy-allo-yohimbane IGfl-carboxylic acids, the monoesters, monoethers, diesters and monoester-monoethers of such compounds, or salts thereof. These compounds may be illustrated by 18,8-organic sulfonyloxy l 7a-lower alkoxy-allo-yohimbanel6 3-carboxylic acid esters, 18u-organic sulfonyloxy-17 a-lower alkoxy-allo-yohimbane -:carboxylic acid esters, 18fl-etherified hydroxy-l7a-lower alkoxy-allo-yohimbane 16,8-carboxylic acid esters or 18a-etherified hydroxy- 7 17a-lower alkoxy-allo-yohimbane 16fi-carboxylic acid esters, or acid addition salts of such compounds.

In these compounds, the l6fi-carboxylic acid esters are primarily lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, esters, as well as lower alkoxy-lower alkyl esters, in which lower alkoXy is separated from the 16fi-carboxyl group by at least two carbon atoms, such as 2-lower alkoxy-ethyl esters, e.g. Z-methoxyethyl, 2- ethoxyethyl and the like, as well as 2-l0wer alkoxy-Z- methyl-ethyl, 3-lower alkoxy-lower alkyl esters and the like. Ethers of the 18-hydr0xyl group are especially lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, nbutyl, n-pentyl, n-hexyl and the like, ethers, as well as lower alkoxy-lower alkyl ethers, in which lower alkyl separates lower alkoxy from the 18-oxygen atom by at least two carbon atoms, such as 2-lower alkoxy-ethyl ethers, e.g. 2-methoxyethyl, 2-ethoxyethyl and the like, as well as 2-lower alkoxy-Z-methyl-ethyl, 3-lower alkoxypropyl ethers and the like. The organic carbonyl portion of any 18-organic carbonyloxy group is represented by the acyl radical of an organic carboxylic acid, such as a lower alkanoic acid, e.g. acetic, propionic, pivalic acid and the like, or, more particularly, a monocyclic carbocyclic aryl carboxylic acid, such as benzoic acid, lower alkyl-benzoic acid, e.g. 3,4,5-trimethyl-benzoic acid and the like, a hydroxy-benzoic acid, e.g. 4-hydroxy-benz0ic acid and the like, a lower alkoxy-benzoic acid, e.g. 3,4-dimethoxybenzoic, 3,4,S-trimethoxy-benzoic acid and the like, a lower alkyl-(lower alkoxy)-benzoic acid, e.g. 3,5-dimethyl-4-methoxy-benzoic acid and the like, a lower alkoxy- (lower alkoxy-carbonyloxy)-benzoic acid, e.g. O-ethoxycarbonyl-syringic acid and the like, an N,N-di-lower alkylamino-benzoic acid, e.g. 3-N,N-dimethylamino-benzoic acid and the like, or a monocyclic carbocyclic aryl-lower alkanoic or a monocyclic carbocyclic aryl-lower alkenoic acid, e.g. 3,4,5-trimethoXy-dihydrocinnamic, 3,4,5-trimethoxycinnamic, O-ethoXycarbonyl-ferulic acid and the like, as well as the acyl radical of a monocyclic heterocyclic aryl carboxylic acid, e.g. nicotinic, isonicotinic, furoic acid and the like, or any other analogous carboxylic acid, used to furnish the acyl radical in an 18-esterified hydroxyl group of known yohimbane compounds. The organic sulfonyl portion of an 18-organic sulfonyloxy group represents the acyl radical of an aliphatic sulfonic acid, such as a lower alkane sulfonic acid, e.g. methane sulfonic, ethane sulfonic acid and the like, or, more especially, of a monocyclic carbocyclic aryl-sulfonic acid, e.g. benzene sulfonic, 4-bromo-benzene sulfonic, 3-nitrobenzene sulfonic, 4-nitro-benzene sulfonic, p-toluene sulfonic acid and the like.

More specific groups of compounds of the above type are the B-iso-reserpic acid,

18-epi-3-iso-reserpic acid,

lower alkyl 3-iso-reserplates,

lower alkyl 18-epi-3-iso-reserpates,

18-O-lower alkyl-3-iso-reserpic acids,

18-epi-O-lower alkyl-3-iso-reserpic acids,

lower alkyl 18-O-lower alkanoyl-3-iso-reserpates,

lower alkyl 18-O-monocyclic carbocyclic aroyl 3-isoreserpates,

loweralkyl 18-O-monocyclic carbocyclic aryl-lower alkenoyl-3-iso-reserpates,

lower alkyl 18-O-lower alkylsulfonyl-3-iso-reserpates,

lower alkyl l8-epi-O-lower alkyl-sulfonyl-3-iso-reserpates,

lower alkyl 18-O-monocyclic carbocyclic aryl-sulfonyl3- iso-reserpates,

lower alkyl 18-epi-O-monocyclic carbocyclic arylsulfonyl-3-iso-reserpates,

lower alkyl 18-O-lower alkyl-3-iso-reserpates,

lower alkyl 18-epi-O-lower alkyl-3-iso-reserpates or analogous compounds of the 3-iso-reserpic and the l8-epireserpic acid series,

or acid addition salts thereof.

Other starting materials are the 3-iso-deserpidic acid, lower alkyl S-iso-deserpidates,

lower alkyl 18-epi-3-iso-deserpidates,

l8-O-lower alkyl-3-iso-deserpidic acids,

18-epi-O-lower alkyl-3-iso-deserpidic acids,

lower alkyl 18-O-l0wer alkanoyl-3-iso-deserpidates,

lower alkyl l8-O-monocyclic carbocyclic aroyl-S-isodeserpidates,

lower alkyl 18-O-monocyclic carbocyclic aryl-lower a1kenoyl-3-iso-deserpidates,

lower alkyl 18-O-lower a1kyl-sulfonyl-3-iso-deserpidatcs,

lower alkyl 18-epi-O-lower alkylsu1fonyl-3-isodeserpidates,

lower alkyl 18-O-monocyclic carbocyclic aryl-sulfonyl-3- iso-deserpidates,

lower alkyl l8-epi-O-monocyclic carbocyclic arylsulfonyl-3-iso-deserpidates,

lower alkyl 18-O-lower alkyl-3-iso-deserpidates,

lower alkyl 18-epi-O-lower alkyl-3-iso-deserpidates and the like,

or analogous compounds of the 3 iso deserpidic and 18 epi 3 iso deserpidic acid series, particularly those in which the 9-position, the 10-position, the ll-position and/ or the l2-position are substituted by lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy and the like, lower alkylenedioxy, e.g. methylenedioxy, l,lethylencdioXy and the like, lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, halogeno, e.g. fiuoro, chloro, bromo and the like, or any other suitable substituent, and/or in which the 5-position and/or the 6-position carries a lower alkyl, particularly methyl, group, and/or in which the l7u-methoxy group is replaced by another lower alkoxy, e.g. ethoxy, n-propyloxy, isopropyloxy and the like, group or by hydrogen, cyano or any other analogous group, or acid addition salts thereof.

Specific examples of such compounds are 3-iso-reserpic acid, methyl B-iso-reserpate, ethyl 3-iso-reserpate, n-propyl 3-iso-reserpate, methyl 18-epi-3-iso-reserpate, ethyl l8-epi-3-iso-reserpate, n-propyl l8-epi-3-iso-rescrpate, 18-O-methyl-3-iso-reserpic acid, l8-O-ethyl-3-iso-reserpic acid, 18-O-n-propyl-3-iso-reserpic acid, 18-epi-O-methyl-3-iso-reserpic acid, l8'epi-O-ethyl-3-iso-reserpic acid, 18-epi-O-n-propyl-3-iso-reserpic acid, methyl 18-O-acetyl-3-iso-reserpate, 3-iso-reserpine, 3-iso-syrosingopine, 3-iso-rescinnamine, methyl 18-O-methyl-sulfonyl-3-iso-reserpate, methyl 18-epi-O-methyl-sulfonyl-3-iso-reserpate, methyl 18-0-(4-bromo-phenyl-sulfonyl)-3-iso-reserpate, methyl 18-0- 3-nitro-phenyl-sulfonyl -3-iso-reserpate, n-propyl 18-O- 3-nitro-phenyl-sulfonyl -3-iso-reserpate, ethyl 18-O-(4nitro-phenyl-sulfonyl)-3-iso-reserpate, methyl 18-epi-0-(4-bromo-phenyl-sulfonyl)-3-isoreserpate, methyl l8-epi-O-( 3-nitro-phenyl-sulfonyl) -3 -iso-rcserpate, npropy1 18 epi O (S-nitro-phenyl-sulfonyl)-3-isoreserpate, ethyl 18-epi-O- (4-nitro-phenyl-sulfonyl -3-iso-reserpate, methyl 18-O-methyl-3-iso-reserpate, ethyl 18-O-ethyl-3-iso-reserpate, methyl 18-epi-O-methyl-3-iso-reserpate, methyl l8-epi-O-ethyl-3-iso-reserpate, methyl 18-epi-O-n-propyl-3-iso-reserpate, or similar monoesters, monoethers, diesters or monoestermonoethers of the 3-iso-reserpic or l8-epi-3iso-reserpic acid type, or analogous monoesters, monoethers, diesters 9 or monoester-monoethers of the 3-iso-deserpidic or 18- epi-S-iso-deserpidic acid series or analogous 3-iso-deserpidic or 18-epi-3-iso-deserpidic acids containing substituents attached to the 5-, 6-, 9-, 10-, 11- and/or l2-positions, as shown hereinbefore and/or having the l7oz-met-hOXy group replaced by another lower alkoxy group, or by hydrogen, cyano and the like, or acid addition salts thereof.

Salts of the starting materials are acid addition salts, for example, the addition salts with the acid used in the reaction medium, e.g. acetic acid and the like, or any other suitable acid addition salts.

Free l8e-hydroxy-allo-yohimbane 16e-carboxylic acids, monoesters and diesters thereof, which are used as starting materials in the above oxidation reaction, are known or may be prepared according to known methods. Monoester-monoethers of such acids may be prepared, for example, by reacting corresponding acid esters with diazocompounds in the presence of fluoboric acid; upon hydrolysis of the resulting monoester-monoethers, monoethers may be formed. l8ot-hydroxy-allo-yohimbane 16;?- carboxylic acids, esters and 18-ethers thereof may be manufactured, for example, by hydrolysis or alcoholysis of a suitable HEB-organic sulfonyloxy-allo-yohimbane 16 8- carboxylic acid ester, preferably in the presence of N,N,N- triethylamine; from a resulting ISu-hydroxy-allo-yohimbane 16(3-carboxylic acid ester the free acid or diesters and from the resulting monoester-monoethers the monoethers of the free acids may be prepared according to known or above-mentio-ned methods.

The invention also includes process for the formation of compounds having the 1,3/3,5,6,l4,l5,16,1 7,18,19,20,21- dodecahydro-benz[g]indolo[2,3-b]quinolizine ring system, which comprises treating a compound having the 1, 3a,5,6,14,15,16,17,18,19,20,21 dodecahydro benz[g]- indolo[2,3-b]quinolizine ring system, or a salt thereof, with an oxidation reagent containing hexavalent chromium and removing in a resulting compound, having the 1,5,6, 15,l6,17,18,19,20,21 dec-ahydro benz[g]-indolo[2,3,-b]- quinolizine ring system, or a salt thereof, the double bond which extends from the 3-position by reduction, and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof.

The above oxidation reaction is carried out according to the previously-given procedure; potassium dichromate in aqueous acetic acid represents the preferred reagent. The removal of the double bond is carried out according to known methods, for example, by treatment with zinc in the presence of an acid or a mixture of acids, such as acetic acid and/or perchloric acid, using water and/or water-miscible organic solvents as diluents.

Salts, N-oxides or salts of N-oxides of resulting compounds are prepared according to known methods.

*In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

This is a continuation-in-part application of our application Serial No. 80,040, filed January 3, 1961 (now abandoned).

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 To a solution of 0.5 g. of 3-iso-reserpine in ml. of acetic acid is added a solution of 0.2 g. of potassium dichromate in 5 ml. of water; the reaction mixture darkens upon addition indicating immediate oxidation. After standing at room temperature for 1 /2 hours, an excess 10 3-dehydro-reserpine; paper chromatography of the reaction mixture shows the latter free from 3-iso-reserpine, used as the starting material. The free base is converted to the perchlorate, which melts at 215218 after recrystallization from a mixture of methanol and isopropanol.

Example 2 To a mixture of 0.4 g. of B-dehydro-reserpine perchlorate in 3.2 ml. of acetone, 1.6 ml. of water and 0.2 ml. of concentrated aqueous perchloric acid (density=1.61), is added 0.4 g. of zinc powder. The reaction mixture is refluxed for about twenty minutes while stirring and maintaining an atmosphere of nitrogen, and is then filtered hot. The solid material is washed with hot acetone; the combined filtrates are cooled and the desired reserpine perchlorate precipitates. Water is added While cooling to 5 and stirring; the solid material is filtered off, washed with water and dissolved in hot aqueous acetone, Concentrated ammonia is added to the warm solution and the desired reserpine precipitates and is purified by recrystallization according to known methods, M.P. 260- 270 (decomposition).

Example 3 To a mixture of 1.0 g. of methyl 3-iso-rese rpate in 20 ml. of acetic acid and 40 ml. of water is added a solution of 0.36 g. of potassium dichromate in 20 ml. of water. The reaction mixture is held at room temperature for one hour, is made basic with ammonia and extracted with methylene chloride, which extract is dried over magnesium sulfate and evaporated under reduced pressure. The desired methyl 3-dehydro-reserpate is crystallized and recrystallized from methylene chloride, M.P. 203-. 206; [a] =-}-1l7 (chloroform).

The resulting methyl 3-dehydro-reserpate may be converted into methyl reserpate according to the procedure described in Example 2.

Example 4 To the mixture of 1.0 g. of methyl 18-epi-3-iso-reserpate in 20 ml. of acetic acid and 40 m1. of water is added 0.4 g. of potassium chromate in 20 ml. of water. The reaction mixture is allowed to stand at room temperature for one hour, 200 mi. of Water is added, and the solution is made basic with ammonia. The desired methyl 3-dehydro-1S-epi-reserpate is extracted with methylene chloride and worked up as shown in Example 3; it melts at 2112l5 after crystallization from a mixture of methanol and water, and its [a] is +110 .(chloroform).

In the above example, potassium 'dichromate may be replaced by ammonium dichromate, lithium dichromate, sodium dichromate, chromic anhydride and the like.

The resulting methyl 3-dehydro-18-epi-reserpate may be converted into the desired methyl 18-epi-reserpate by treatment with zinc in the presence of aqueous perchloric acid according to the method described in Example 2..

Example 5 To a mixture of 0.8 g. of methyl l8-epi-O-methyl-3- iso-reserpate in 16 ml. of acetic acid and 32 ml. of water s added a solution of 0.32 g. of potassium dichromate in 16 ml. of water. After standing at room temperature for one hour, the solution is made basic with aqueous ammonia, the organic material is extracted with methylene chloride, and the organic solution is dried over sodium sulfate and evaporated to dryness. The residue is crystallized from methanol to yield the desired meth yl 18-epi O methyl-3-dehydro-reserpate, M.P. 226-231", [a] (in chloroform).

Example 6 A mixture of 0.5 g. of methyl l8-epi-O-methyl-3-dehydro-reserpate, 5 ml. of tetr-ahydrofuran, 5 ml. of acetone, 4.5 m1. of water, 0.6 ml. of aqueous perchloric acid (of II to III). The chromatogram is developed as follows:

Fractions Solvents Eluted Amounts 50 ml. of benzene no residue. o 0. 035 g. rln smear.

50 ml. of methylene chloride 0. 185 g: do 0.080 g. 100 ml. of methylene chloride, containing 1 0.180 g.

percent of methanol. 100 ml. of methylene chloride, containing 5 0.010 g.

percent of methanol. 8- 100 ml. otmethanol smear.

Fraction 6 is crystallized from diethyl ether to yield 0.15 g. of methyl l8-epi-O-methyl-reserpate, M.P. 233236, [a] =-38 (in chloroform).

Example 7 To a mixture of 0.8 g. of methyl l8-O-methy1-3-isoreserpate in 16 ml. of acetic acid and 32 ml. of water is added 0.32 g. of potassium dichromate in 16 ml. of water. The reaction mixture is allowed to stand at room temperature and is made basic with aqueous ammonia, whereupon a yellow solid precipitates; the organic material is extracted with methylene chloride, and the extract is dried over sodium sulfate and evaporated to dryness. The desired methyl 18-O-methyl-3-dehydro-reserpate crystallizes from ethyl acetate, M.P. 20l205, [a] =+12Z (chloroform) Example 8 To a solution of 0.75 g. of methyl 18-O-methy1-3-dehydro-reserpate in a mixture of 8 ml. of tetrahydrofuran, 8 ml. of acetone and 7.2 ml. of water are added 0.8 ml. of concentrated perchloric acid of about 70 percent strength and then 0.7 g. of powdered zinc. The mixture is refiuxed while constantly stirring for fifteen minutes under an atmosphere of nitrogen, and then evaporated to dryness under reduced pressure. The oily residue is dissolved in 20 m1. of a 3:2-mixture of acetone and water, the solution is made basic with aqueous ammonia and the organic solvent is evaporated 0135. 25 ml. of water is added, the organic material is extracted with methylene chloride and the organic solution is dried over sodium sulfate and then evaporated to dryness to leave 0.72 g. of a foamy material.

The residue is chromatographed on 20 g. of alumina (Woelm, neutral, activity 11 to H1). The following fractions are collected and each of the fractions subjected to paper chromatography in the system chloroform/formamide to determine the identity of the various fractions:

12 Fractions 2 to 7, inclusive, are combined and dissolved in a hot 1:3-mixture of benzene and cyclohexane, and the solution is concentrated until crystalline material is formed. A first crop of 0.35 g., representing methyl IS-O-methylreserpate, melts at 230233 and has a rotation of Example 9 To a mixture of 2.0 g. of 2-methoxyethyl 18-epi-3-isoreserpate in 40 ml. of acetic acid and ml. of water is added 0.72 g. of potassium chromate in 40 ml. of water; the reaction mixture is allowed to stand at room temperature for one hour and then worked up as shown in Example 3. The desired 2-methoxyethyl 3-dehydro-18-epireserpate melts at l74 after crystallization from methanol; [a] =+l25 (chloroform), and may be converted into the Z-methoxyethyl l8-epi-reserpate according to the procedure described in Example 2.

Example 10 A mixture of a solution of 1.0 g. of 2-methoxyethyl 18-epi-O-ethyl-3-iso-reserpate in 20 ml. of acetic acid and 40 ml. of water and 0.4 g. of potassium dichromate in 20 m1. of water is allowed to stand at room temperature for one hour and is then worked up as shown in Example 3. The desired Z-methoxyethyl 18-epi-O-ethyl-3-dehydro-reserpate, obtained as a foam, is used without further purification in the reduction to the 2-methoxyethyl 18-epi-O-ethyl-reserpate according to the procedure of Example 2.

What is claimed is:

1. In the process for the preparation of a compound having as the ring system a member selected from the group consisting of the 1,5,6,15,16,17,18,19,20,21-decahydro-benz[g]indolo[2,3-a]quinolizine ring system having a double bond in the 3(14)-position, and the 5,6,14,15, 16,17,l8,19,20,21 decahydro 1H benz[g]indolo[2,3- a]quinolizine ring system having a double bond in the 3(4)-position, the step which comprises reacting at room temperature a member selected from the group consisting of a compound having the 1,3a,5,6,14,l5,16,l7,18,l9, 20,21 dodecahydro benz[g]indolo[2,3 a]quinolizine ring system, and an acid addition salt thereof, with an oxidation reagent containing hexavalent chromium selected from the group consisting of a salt of chromic acid and chromic anhydride, in the presence of an aqueous medium consisting of a mixture of water and a water-miscible organic solvent.

2. Process according to claim 1, which comprises using an alkali metal dichromate as the oxidation reagent.

3. Process according to claim 2, which comprises us ing potassium dichromate as the oxidation reagent.

4. Process according to claim 1, which comprises carrying out the reaction in the presence of aqueous acetic acid as the mixture of water and a water miscible solvent.

5. In the process for the preparation of a member selected from the group consisting of a A -18-hydroxyallo-yohimbene 16B-carboxy1ic acid and a A -18-hydroxy-allo-yohimbene lop-carboxylic acid and a monoester, a monoether, a diester and a monoester-monoether of such compounds, the step which comprises treating at room temperature a member selected from the group consisting of an 18-hydroxy-allo-yohimbene 16fl-carboxylic acid, a monoester, a monoether, a diester and a moneester-monoether thereof, and a salt of such compound, with a salt of chromic acid in the presence of an aqueous medium consisting of water and a water-miscible organic solvent.

6. Process according to claim 5, which comprises using potassium dichromate as a salt of chromic acid.

7. Process according to claim 5, which comprises using aqueous acetic acid as the aqueous medium.

8. Process for the prepartion of a compound having 13 the 1,3B,5,6,14,15,16,17,18,19,20,21 dodecahydro benz [g]indolo[2,3-a1quinolizine ring system, which comprises treating at room temperature a member selected from the group consisting of a compound having the 1,3oc,5,6, 14,15,16,17,18,19,20,21 dodecahydro benz[g]indolo[2, 3-a]quinolizine ring system, and a salt thereof with an oxidation reagent containing hexavalent chromium selected from the group consisting of a salt of chromic acid and chromic anhydride, in the presence of an aqueous medium consisting of a mixture of water and a watermiscible organic solvent, and reducing in a resulting member selected from the group consisting of a compound having the 1,5,6,15,16,17,18,19,20,21 decahydrobenz[g]ind01o[2,3-a]quinolizine ring system, and a salt thereof, the double bond extending from the 3-position by treatment with zinc in the presence of a member se- References Cited in the file of this patent UNITED STATES PATENTS Weisenborn et a1 Mar. 28, 1961 OTHER REFERENCES Theilheimer: Syn. Methods of Org. Chem., volume 9 (1955), page 407.

Wenkert et al.: Jour. Amer. Chem. Soc., volume 79 (1957), pages 1519 and 1520. 

1. IN THE PRECESS FOR THE PREPARATION OF A COMPOUND HAVING AS THE RING SYSTEM A MEMBER SELECTED FROM THE GROUP CONSISTING OF THE 1,5,6,15,16,17,18,19,20,21-DECAHYDRO-BENZ(G)INDOLO(I,3-A)QUINOLIZINE RING SYSTEM HAVING A DOUBLE BOND IN THE 3(14)-POSITION, AND THE 5,6,14,15, 16,17,18,19,20,21 - DECAHYDRO - 1H - BENZ(G)INDOLO(2,3A)QUINOLIZINE RING SYSTEM HAVING A DOUBLE BOND IN THE 3(4)-POSITION, THE STEP WHICH COMPRISES REACTING AT ROOM TEMPERATURE A MEMBER SELECTED FROM THEGROUP CONSISTING OF A COMPOUND HAVING THE 1,3A,5,6,14,15,16,17,18,19, 20,21 - DODECAHYDRO - BENZ(G)INDOLO(2,3 - A)AQUINOLIZINE RING SYSTEM AND AN ACID ADDITION SALT THEREOF, WITH AN OXIDATION REAGENT CONTAINING HEXAVALENT CHROMIUM SELECTED FROM THE GROUP CONSISTING OF A SLAT OF CHROMIC ACID AND CHROMIC ANHYDRIDE, IN THE PRESENCE OF AN AQUEOUS MEDIUM CONSISTING OF A MIXTURE OF WATER AND A WATER-MISCIBLE ORGANIC SOLVENT. 